Oncogenic KRAS is found in 25% of patient tumors across many cancer types. Despite extensive effort since its discovery over 30 years ago there is still no effective treatment for KRAS tumors. An estimated 350,000 patients in the US in 2013 will be diagnosed with mutated KRAS in their tumor, and many will die of their disease. Mutated KRAS plays a critical role in driving tumor growth and resistance to therapy. Its effects are so powerful that it overrides the activity of many of the new molecularly targeted signaling drugs being developed for cancer. Thus, finding new agents that inhibit the effects of mutated KRAS is one of the most important unmet medical needs in cancer today. Mutated KRAS as a target also presents an untapped business opportunity because of the large number of patients that could benefit from an effective inhibitor, used alone or in combination with molecularly targeted therapies from which the patients are currently excluded. PHusis Therapeutics has adopted a new paradigm for attacking KRAS tumors through inhibition of critical KRas associated regulatory proteins as surrogate targets for inhibiting KRas signaling activity and cell growth. Using functional genomic screening PHusis has identified PLEKHA7, a protein associated with the mutated KRas signaling nanocluster, as a top hit and has shown that PLEKHA7 is absolutely necessary for the growth and down-stream signaling activity of mutated KRas in cancer cells. Remarkably inhibiting PLEKHA7 is without effect on wild type KAS cancer cell growth. PHusis has validated PLEKHA7 as an essential mutated KRas regulator protein using extensive molecular, cellular and in vivo studies. The PLEKHA7 protein has a unique 3D fold, the pleckstrin homology (PH) domain that binds to phosphoinositide lipids thus positioning host proteins at specific sites in the cell membrane. The mechanism, we propose for PLEKHA7 is that its PH domain is necessary to correctly position the mutated KRas signaling nanocluster at sites in the plasma membrane where it drives cancer cell growth and invasion. PHusis Therapeutics has extensive experience developing PH domain inhibitors and has been able to show that the PH domain of PLEKHA7 is a druggable entity, and has developed proof of principle low micromolar selective small molecule leads using computational docking and a homology model of the PLEKHA7 PH domain. PHusis now has in hand a 1.4-Angstrom X-ray crystal structure of the PLEKHA7 PH domain and will use it to design proprietary, higher affinity inhibitors of PLEKHA7 that selectively block the growth of mutant KRAS cancer cells. Thus, the hypothesis upon which the studies are based is There is no effective therapy for oncogenic KRAS tumors. PLEKHA7, acting through its PH domain, is necessary for mutant KRas but not wild type KRas, signaling, cell proliferation and tumor growth. PLEKHA7 has a unique druggable PH domain that is required for PLEKHA7's facilitation of mutant KRas signaling providing a window of opportunity to develop small molecules inhibitors as potential agents for the treatment of KRas tumors. Thus the objectives of the Phase I SBIR study are: 1) to use the newly developed X-ray crystal structure of the PLEKHA7 PH domain to design more potent, selective and drug-like small molecule inhibitors and confirm their binding by co-crystallization studies; 2) to test the ability of the agents to selectively inhibit mutated KRAS signaling and cell growth; an 3) to conduct a proof of principle in vivo pilot study of the most active compound as an inhibitor of a mutant KRas tumor growth.